Adenoviruses (Ads) are the most widely used vectors in gene therapy. They have the advantages of having the ability to infect a wide range of dividing and non-dividing cells, of being easily produced to high titers, and of having well characterized strains used for construction of recombinant viruses (especially the ones being commonly used in gene therapy such as Ad2, Ad5). The first generation E1/E3 deleted vectors can accommodate ˜8 kb of inserts whereas helper dependent Ads can accommodate up to 37 kb of foreign genetic material.16 
Ads were first isolated and cultured in 1953 from adenoid cells and to date 55 human adenovirus serotypes have been identified and grouped in six species (A-F). Most of these serotypes cause mild infection of the upper respiratory tract, gastroenteritis or conjunctivitis. Moreover, wildtype (WT) adenovirus has been used as a vaccine for US military recruits and showed to cause very few side effects. This contributed to the idea that Ads are safe viruses to use for human gene therapy, although high doses of adenovirus may cause an overwhelming immune response.17, 18, 19 However, local ex vivo gene transfer reduces these problems.
A significant limitation of using Ads as vectors clinically is the high rates of pre-existing neutralising antibodies in most humans leading to rapid neutralization upon administration in the circulation. Furthermore, upon administration into in the circulation the majority of virus particles are rapidly sequestered by the liver, thus failing to reach their target cells or tissues to a sufficient extent for their intended purpose. Moreover, increasing the vector dosage as an attempt to overcome these problems has proven to be inadequate and sometimes toxic, or even lethal.
Adenovirus serotype 5 (Ad5) is widely used for vascular gene transfer, where delivery of therapeutic transgenes to prevent excessive smooth muscle cell proliferation can prevent neointimal thickening and thus graft failure following coronary bypass procedures. However, uptake of adenovirus into the vessel wall and the resulting level of gene transfer mediated through Ad5 is relatively poor and necessitates high input titers of virus. Additionally, a significant proportion of patients present pre-existing neutralising antibodies against Ad5.
Collectively, these sub-optimal characteristics of Ad5 limit the progression and interpretation of vascular gene therapy in the clinical setting. Thus, identification and development of more efficient vectors is needed.
Some workers have moved towards vectors based on other virus types entirely. Those choosing to persist with adenoviruses have adopted strategies including use of chimeric human Ads (Ad pseudotypes), non-human Ads, or Ad vectors with low seroprevalence in order to avoid the immune response and detarget the vectors away from the liver and retarget them to cells and tissues of interest.
However, the human adenovirus family is extensive with many rare and understudied adenoviruses (currently 55 known serotypes). At present, little is known about their tropism or potential for use as novel vectors, seriously limiting their practical application.